Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors
Open accessAbstract
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an extended polyglutamine repeat in the N terminus of the Huntingtin protein (HTT). Reactive microglia and elevated cytokine levels are observed in the brains of HD patients, but the extent to which neuroinflammation results from extrinsic or cell-autonomous mechanisms in microglia is unknown. Using genome-wide approaches, we found that expression of mutant Huntingtin (mHTT) in microglia promoted cell-autonomous pro-inflammatory transcriptional activation by increasing the expression and transcriptional activities of the myeloid lineage-determining factors PU.1 and C/EBPs. We observed elevated levels of PU.1 and its target genes in the brains of mouse models and individuals with HD. Moreover, mHTT-expressing microglia exhibited an increased capacity to induce neuronal death ex vivo and in vivo in the presence of sterile inflammation. These findings suggest a cell-autonomous basis for enhanced microglia reactivity that may influence non-cell-autonomous HD pathogenesis.
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Seven genes (Syk, Lyn, Stat1, Entpd1, Rgs10, Fcgr1, and Fcgr3) are directly targeted by Spi1 and may be involved in phagocytosis.
“Based on the “Immune response_Phagocytosis” components and the Spi1 chromatin immunoprecipitation sequencing (ChIP-Seq) data38,39, we selected seven genes (Syk, Lyn, Stat1, Entpd1, Rgs10, Fcgr1, and Fcgr3) that are directly targeted by Spi1 and may be involved in phagocytosis.”
From Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models (2026) · cites this paper as [38]
The Results section on mHTT-promoted PU.1–C/EBP gene expression reports PU.1 ChIP-seq data in microglia, supporting the citation as a source of Spi1/PU.1 binding data (page unavailable). Our copy does not identify the seven named genes as direct targets or link them to phagocytosis; searches for the gene list, Fcgr3, and phagocytosis did not locate that evidence. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe beneficial effects of A11 might stem from a reduction in PU.1 activity below a threshold that otherwise causes microglia to acquire a detrimental and hyperinflammatory phenotype or that helps undo unresolved microglial activation.
“The beneficial effects of A11 might stem from a reduction in PU.1 activity below a threshold that otherwise causes the microglia to acquire a detrimental and hyperinflammatory phenotype (Crotti et al., 2014; Gjoneska et al., 2015) or that helps the undoing of unresolved microglial activation (Leng and Edison, 2021).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Crotti et al., 2014
The Results report that knocking down PU.1 greatly reduced IL-6 and TNF-α expression in mutant-huntingtin microglia, and the Discussion links increased PU.1 to pro-inflammatory and neurotoxic activity. Crotti et al. do not establish a PU.1 activity threshold or show that crossing one causes microglia to acquire that phenotype. The proposed benefit of A11 is the citing authors’ inference, while the unresolved-activation clause is attributed to a different source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPU.1 activity is increased in mouse models of neurodegeneration.
“PU.1 activity is increased in mouse models of neurodegeneration (Crotti et al., 2014; Gjoneska et al., 2015)”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Crotti et al., 2014
In Results (‘PU.1-C/EBPs-induced inflammatory transcription is specific for mHTT in vivo’; page not provided), the paper reports increased PU.1-encoding Sfpi1 and target-gene expression in a Huntington’s disease mouse model. The same section reports no such increase in an ALS mouse model, so the unqualified claim about mouse models of neurodegeneration is broader than this source supports. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEx vivo and in vivo studies showed that mHTT-expressing microglia are more toxic to neurons than WT microglia after pro-inflammatory stimuli.
“Moreover, ex vivo and in vivo studies showed that mHTT-expressing microglia are more toxic to neurons than WT microglia after pro-inflammatory stimuli.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [445]
Microglia expressing mHTT exhibit an intrinsic pro-inflammatory gene expression profile even without pro-inflammatory stimuli.
“Using genome-wide approaches, one study revealed that microglia expressing mHTT exhibited an intrinsic pro-inflammatory gene expression profile even without pro-inflammatory stimuli.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [445]
Endogenous mutant huntingtin alone alters the microglial transcriptional landscape through increased expression of Pu.1, resulting in enhanced production of Il6 and Tnf transcripts and increased neurotoxicity in the context of a secondary immune challenge.
“While microglia conventionally react to stress signals and exogenous toxins in neurodegeneration, the presence of endogenous mHTT alone alters their transcriptional landscape through increased expression of the myeloid lineage-determining factor Pu.1 (Crotti et al. , 2014), resulting in enhanced production of Il6 and Tnf transcripts as well as increased neurotoxicity in the context of a secondary”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Crotti et al., 2014
In R6/2 microglia, mutant HTT primes the cells by raising Pu.1, a myeloid transcription factor that promotes phagocytosis.
“Mutant HTT expression in R6/2 microglia effectively 'primes' the cell by increasing expression of the myeloid transcription factor Pu.1”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Crotti et al., 2014
ATAC-seq can evaluate transcriptional networks controlling the microglial signature at an epigenetic level by determining chromatin accessibility.
“In addition to FACS and immunohistochemical approaches, assay for transposase accessible chromatin sequencing (ATAC-seq) can evaluate transcriptional networks that control microglial signature at an epigenetic level determining the chromatin accessibility landscape in microglia [5, 22, 23].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [23]
iMGLs can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB.
“In addition to AD GWAS genes, iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS and therefore, can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB in which microglia may play a prominent role (Bachstetter et al., 2015; Crotti et al., 2014; Lui et al., 2016; O’Rourke et al., 2016)(Figure S6C).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Crotti et al., 2014
iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS.
“In addition to AD GWAS genes, iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS and therefore, can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB in which microglia may play a prominent role (Bachstetter et al., 2015; Crotti et al., 2014; Lui et al., 2016; O’Rourke et al., 2016)(Figure S6C).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Crotti et al., 2014
Dysregulation of microglia functions contributes to the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and Huntington's disease.
“Dysregulation of microglia functions contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD) (6–8), Parkinson’s disease (PD) (9–12) and Huntington’s disease (HD) (13–15).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [13]
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References 55 · Cited by 333
Research works printed but not linked: 1
- [45]Bjorkqvist M A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease J Exp Med 205 1869 1877 2008 18625748 PMC2525598
- Authors
- Crotti, A., Benner, C., Kerman, B. E., Gosselin, D., Lagier-Tourenne, C., Zuccato, C., Cattaneo, E., Gage, F. H., Cleveland, D. W., & Glass, C. K.
- Affiliations
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- University of Milan (IT)
- Corresponding author
- Glass, Christopher K
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2014-03-02
- Volume
- 17
- Issue
- 4
- Pages
- 513-521
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4113004
- OpenAlex
- W2133775329
- Cited by
- 333
- References
- 55
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 26 · 2023: 25 · 2022: 26 · 2021: 25 · 2020: 30 · 2019: 36 · 2018: 34 · 2017: 27 · 2016: 26 · 2015: 29 · 2014: 11
- FWCI
- 16.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Wellcome Trust (089701)
- National Institute of Mental Health (R24MH068855, PHS R24 MH068855)
- National Cancer Institute (R01CA173903, CA17390)
- National Institute of General Medical Sciences (U54GM069338, GM 069338)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, DK091183, P30DK063491, R01DK091183)
- National Institute of Neurological Disorders and Stroke (R37NS027036)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- mutant huntingtin, Huntington's disease, microglial activation, PU.1, C/EBP, neuroinflammation, neuronal cell death, sterile inflammation, polyglutamine repeat
- MeSH terms
- Huntingtin Protein, Animals, Disease Models, Animal, Humans, Huntington Disease, Inflammation, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Cell Death, Microglia, Myeloid Cells, DNA Repeat Expansion, Mice, Genome-Wide Association Study, Gene Knock-In Techniques
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